Optimal strategy of primary percutaneous coronary intervention for acute myocardial infarction due to unprotected left main coronary artery occlusion (OPTIMAL): study protocol for a randomised controlled trial

The aim of this open-label, multicenter RCT is to compare immediate stenting with deferred stenting for LM-AMI in 30 hospitals in China. We hypothesize that patients with LM-AMI receiving deferred stent implantation will have improved short-term and long-term clinical outcomes compared with those receiving immediate stenting. A total of 480 patients with diagnosed LM-AMI will be randomly assigned in a 1:1 ratio to either deferred stenting or immediate stenting and followed for up to 12 months.

Patients with LM-AMI will be consecutively enrolled from 30 clinical centers in China. We recruited participating centers on a voluntary basis. Four centers were not included in the trial, because the numbers of PPCI per year in these centers were less than 50 and they may not have enough experience in treating LM-AMI. The participating centers are located mostly in southern China (20 out of 30) while several other hospitals (10 out of 30) from northern districts are also involved (Additional file 1: Table S1). Most of them are third-grade class-A hospitals (25 out of 30). All participating centers can perform PPCI in 24 h, 7 days a week, and had a minimum volume of 500 PCI procedures and 50 PPCI procedures annually. Coronary care unit and surgery backup are available in all of the centers involved. Additionally, chest pain centers and quick-reaction systems of PCI for patients with AMI have been established among all of these centers. The study protocol and documents have been distributed to the investigators of each center. The OPTIMAL (Optimal Strategy of Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction due to Unprotected Left Main Coronary Artery Occlusion) staff of physicians completing the protocol are responsible for online training and problem solving. Recruitment started on November 1, 2017 and will terminate when the estimated number of patients is reached and we estimate that this will take 3-4 years. Patients are eligible for enrollment if AMI is diagnosed within 12 h and primary angiography shows left main coronary artery occlusion and they reach TIMI 3 flow after reperfusion treatment of balloon dilatation or optional thrombus aspiration or both (Table 1) [20]. Patients with AMI including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) will be enrolled in the study because a certain number of patients with left main coronary artery occlusion present with NSTEMI instead of STEMI. Patients who are more than 80 years old and have malignant tumor, end-stage organ failure, or other terminal diseases are excluded from the study for their shorter life expectancy, more clinical complications, and less availability to complete the follow-up. In addition, patients who cannot tolerate PPCI and anti-platelet therapy or who are included in other ongoing trials will not be eligible. Both peri-procedural and long-term outcomes will be recorded in the 12-month follow-up. Written informed consent is obtained before primary angiography.

Eligible patients will be randomly assigned 1:1 to immediate stenting or deferred stenting after primary angioplasty and informed consent (Fig. 1). Random allocation sequence has been generated by using a computer-based system before recruitment started, and results are encrypted and uploaded to a network accessible to all research centers routinely in stacks of sealed electronic envelopes that can be uncovered only with passwords when patients are enrolled. The block size is 4. When a patient is eligible in one center, the investigators of that center will download and open the electronic envelope with passwords obtained from the system and get the result of random allocation and will report the information of enrollment in an online research database which will inform all of the other investigators.

PCI procedures are performed in accordance with each clinical center’s standard routines. There are no restrictions on the balloons, guide wires, thrombus aspiration, or intra-aortic balloon pump usage. The choice of transradial or transfemoral approach will be determined by the operator. We recommend that the participating centers apply the minimalist immediate mechanical intervention (MIMI) technique with small balloon dilatation and thrombus aspiration for the pretreatment. New-generation drug-eluting stents are applied in all participating centers, and the exact type and size of the stents are possibly different. For immediate stenting, stents are implanted immediately after blood flow is regained by interventional pretreatment. Deferred stenting is scheduled 4–15 days after primary angioplasty and in the same hospitalization period. Immediate stenting will be applied if TIMI grade 3 flow cannot be retrieved and these cases will not be enrolled in analysis. CABG is considered as an alternative and will be scheduled within 6 h after PCI procedure failure. For the deferred stenting group, stent implantation will be canceled at the operator’s discretion if the patient is unsuitable for deferred stenting or stent implantation is unnecessary during the second PCI. These patients will be excluded from the per-protocol set but will still be in the intention-to-treat set.

All patients will be transferred to the coronary care unit after the primary angiographic procedure. Intravenous glycoprotein IIb/IIIa inhibitor will be maintained for 18–36 h after PPCI. A loading dose of aspirin and P2Y12 inhibitors will be given before the procedure. An intravenous bolus of unfractionated heparin (100 U/kg) will be administrated right before the procedure to achieve therapeutic activated clotting time. Dual-anti-platelet therapy will be maintained during the deferred period and for at least 1 year after PCI. The peri-procedural treatment is in accordance with the Chinese guidelines for the management of AMI [21].

The annual primary outcome event rate is 22.9%, which we estimated through integrating results of several observational trials [7, 22‐26]. Because research data about stent implantation in patients with LM-AMI cannot be found, we have to use the data from other trials that enrolled only a few patients with LM-AMI. According to the results of the OPTIMAL study and the experience of our center, we determined a 35% relative decrease in primary outcome, which is conservative given the high mortality and incidence of adverse events for LM-AMI [15]. The study planned to enroll 240 patients for each arm given a 10% rate of loss (two-sided alpha of 0.05 and 80% power to demonstrate the relative decrease).

Both peri-procedural and mid-term clinical outcomes are included in the follow-up plan (Fig. 2). All patients will be followed for 12 months. Patients will receive a mail message and phone call 2 weeks in advance to remind them of the time point for following up. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklist is in presented in Additional file 2.

Patients’ baseline characteristics are collected with case report forms (CRFs) during hospitalization at least 24 h after PPCI by investigators of each center. Angiographic data are recorded in the PCI procedure. According to the follow-up plan, patients are required to undergo recording of history and echocardiogram in each center at 1- and 12-month follow-up.

Data as outlined above will be collected with electronic CRFs by investigators and research coordinators and transferred to an encrypted online database operated by Zhongshan Hospital. The original CRFs and other records of data will be uploaded to the database. Data usage adheres to local laws and regulations of participating centers. Patient privacy is protected by restricting the access to dataset to relevant individuals—investigators, statistical analyzers, clinical research associates (CRAs), and representatives of the ethics committee—and replacement of the actual names in the documents with serial numbers. Representatives of participating centers are responsible for collecting data of enrolled patients in that center and uploading to the database. Angiographic and echocardiographic data are stored in CD-ROMs and sent to a core lab in Zhongshan Hospital, where the data are analyzed by specialists blinded to random allocation.

The statistical analyses of primary and secondary outcomes will be conducted in both the intention-to-treat set and the per-protocol set. According to the intention-to-treat principle, all of these eligible patients who actually did not receive deferred stenting will still be included in the intention-to-treat analysis. In the per-protocol set, patients who undergo randomization but withdraw consent to participate or not treated according to the allocated procedure after randomization will be excluded from per-protocol statistical analyses.

An independent CRA will monitor the study process and verify protocol compliance every 6 months. The CRA has access to all documents in the database, including original medical history, images, and CRFs. Data correctness will be assessed and serious adverse events will be reported to the ethics committee of the particular center and Zhongshan Hospital. The ethics committee of Zhongshan Hospital has the authority to terminate the trial according to local laws or institutional regulations. The investigators should keep the participating centers, ethics committee, and the journal informed of any major protocol modifications.

This study is conducted in accordance with the ethical principles of the Declaration of Helsinki (2013). The protocol of this study has been read and approved by the ethics committee of participating hospitals. Printed informed consent and detailed information about the study will be offered to patients before randomization. The safety and feasibility of deferred stent implantation have been confirmed by several trials in patients with AMI [14, 15, 18]. All information and data of this trial are encrypted and stored in an online database accessible only to main researchers and administrators.

Patients primarily enrolled have rights to withdraw at any time point and the reasons will be documented. If patients in the deferred stenting group decided to withdraw between primary angiography and secondary PCI, stent implantation or CABG is still available for them while follow-up will be cancelled. In addition, PCI or CABG is ready for any patients presenting with recurrent ischemia and MI after stent implantation in the hospital.